Isothiazolones

ABSTRACT

Isothiazolones having the general structure ##STR1## where A is a monocyclic or bicyclic ring which may contain up to 3 heteroatoms selected from O, S, and N; R 1  and R 2  are substituent groups such as alkyl, alkoxy, hydroxy, nitro, cyano, amino, and carboxy; and R 5  is alkyl, cycloalkyl, phenyl, and Het. The isothiazolones are useful as anti-retroviral agents, anti-inflammatory agents, and anti-atherosclerotic agents.

FIELD OF THE INVENTION

This invention provides isothiazolone derivatives which are useful asantiviral agents, anti-inflammatory agents, and anti-atheroscleroticagents. The invention is more particularly directed to bicyclic andpolycyclic isothiazolones which are useful for treating retroviruses,including myeloblastosis associated virus, Rous sarcoma virus, humanT-cell leukaemia virus, and HIV. The compounds also are effective fortreating inflammation and atherosclerosis.

BACKGROUND OF THE INVENTION

Certain isothiazolones are known which have various pharmaceuticalutilities, most notably antimicrobial activity. Okachi, et al., J. Med.Chem., 1985;28:1772-1779, describe several 1,2-benzisothiazolones whichhave marginal antibiotic activity and which were primarily utilized asintermediates in the synthesis of 2,2'-dithiobis (benzamide)derivatives. Carmellino, et al., Eur. J. Med. Chem., 1994;29:743-751,disclose a variety of 1,2-benzisothiazolones as antibacterial andantifungal agents. Miller, et al., U.S. Pat. No. 3,517,022, disclose2-carbamoyl-1,2-benzisothiazolones which are said to be active againstbacteria, fungi, and algae. Morley, in U.S. Pat. No. 3,012,039,describes 2-alkyl-1,2-benzisothiazolones which are useful asantibacterials and antifungals. Sherba, et al., U.S. Pat. No. 5,219,875,describe synergistic antimicrobial compositions comprising2-unsubstituted 1,2-benzisothiazolin-3-one and iodopropargylbutylcarbamate. Laber, et al., U.S. Pat. No. 4,049,817, describesynergistic antimicrobial compositions containing a variety of2-substituted and 2-unsubstituted benzisothiazolinones.

Grivos, U.S. Pat. No. 3,761,489, describes a series of substitutedN-alkyl benzisothiazolinones which are said to be active againstbacteria, fungi, and yeasts. Grivos, U.S. Pat. No. 3,661,974, describesthe synthesis of various 2-substituted 1,2-benzisothiazolin-3-ones from2-carbalkoxy-phenyl sulfonamides. The thiazolinones are said to beuseful as antibacterials and antiseptics.

None of the references describing isothiazolones have disclosed thatsuch compounds can be used to treat and prevent viral infections,inflammation, or atherosclerosis. We have now discovered thatisothiazolones are potent anti-retroviral agents, and an object of thisinvention is to provide a method for preventing and treating viraldiseases, including diseases caused by human T-cell leukaemia virus,Rous sarcoma virus, the myeloblastosis associated virus, various animalretroviruses, as well as HIV. A further object of the invention is toprovide certain isothiazolones which are new compounds and which areespecially useful for treating diseases caused by HIV. Still, a furtherobject is to provide a method for treating inflammation andatherosclerosis by administering an isothiazolone.

SUMMARY OF THE INVENTION

This invention provides a method for preventing and treating retroviralinfections, inflammation, and atherosclerosis comprising administeringto a subject in need of treatment an effective amount of anisothiazolone. The invention is more particularly directed to a methodof preventing and treating retroviral infections, inflammation, andatherosclerosis comprising administering a compound of Formula I##STR2## wherein:

A is a monocyclic ring having 5 or 6 ring atoms, or a bicyclic ringhaving from 9 to 12 ring atoms, the ring atoms being selected fromcarbon and optionally up to 3 heteroatoms selected from O, S, and N.

R¹ and R² independently are hydrogen, halo, C₁ -C₆ alkyl, C₃ -C₆cycloalkyl, Het(CR⁶ R⁷)_(m) -, phenyl-(CR⁶ R⁷)_(m) -, O--C₁ -C₆ alkyl,hydroxy, nitro, cyano, NR³ R⁴, NR³ COR⁴, CO₂ R³, CONR³ R⁴, S(O)_(m) R³,SO₃ H, S(O)_(m) NR³ R⁴, COR³, or taken together are oxo (O═) ormethylene dioxy (--O--CH₂ --O--);

m is 0, 1, or 2;

R³ and R⁴ independently are hydrogen, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl,Het(CR⁶ R⁷)_(m) -, or phenyl-(CR⁶ R⁷)_(m) -;

R⁶ and R⁷ independently are hydrogen, C₁ -C₆ alkyl, CO₂ R³, hydroxy,CONR³ R⁴, or cyano;

R⁵ is hydrogen, C₁ -C₆ alkyl, COC₁ -C₆ alkyl, C₃ -C₆ cycloalkyl,phenyl-(CR⁶ R⁷)_(m) -, Het(CR⁶ R⁷)_(m) -; and

wherein the foregoing alkyl, cycloalkyl, phenyl, and Het groups mayoptionally be substituted with from 1 to 3 groups selected from halo,hydroxy, nitro, NR³ R⁴, NR³ COR⁴, CO₂ R³, CONR³ R⁴, S(O)_(m) R³,S(O)_(m) NR³ R⁴, and COR³, where m, R³, and R⁴ are as defined above;

and the pharmaceutically acceptable salts and solvates thereof.

In a preferred embodiment, the isothiazolones utilized in the methods ofthis invention have Formula I above wherein A is a monocyclic ringhaving 6-ring atoms, one or two of which are heteroatoms selected fromO, S, and N; ideally N.

In a further preferred embodiment, A is a monocyclic aromatic ringhaving 6-ring atoms, one or two of which are O, S, or N; ideally N.Especially preferred compounds within this group have the formulas##STR3##

In another preferred embodiment, the isothiazolones utilized in themethods of the invention are benzisothiazolin-3-ones of Formula II##STR4## where

R¹ and R² independently are hydrogen, halo, C₁ -C₆ alkyl or O--C₁ -C₆alkyl, and R⁵ is C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, orunsubstituted or substituted phenyl-(CR⁶ R⁷)_(m) -.

An especially preferred method for treating viral infections,inflammation, and atherosclerosis employs a compound having the FormulaIII ##STR5## where R¹ is hydrogen, halo, alkyl or alkoxy, and R⁵ is C₁-C₆ alkyl substituted with 1 or 2 CO₂ R³ groups, or phenyl substitutedwith S(O)_(m) NR³ R⁴, where R³ and R⁴ are as defined above.

Another preferred method for treating viral infections, inflammation,and atherosclerosis employs a compound of Formula IVa and Formula IVb##STR6## where R¹, R², and R⁵ are as defined above.

The invention additionally provides a method for preventing and treatingdiseases caused by retroviruses, especially HIV.

Another embodiment of the invention are new chemical compoundscharacterized as isothiazolones of Formula V ##STR7## wherein

A is a monocyclic ring having 5 or 6 ring atoms, or a bicyclic ringhaving from 9 to 12 ring atoms, the ring atoms being selected fromcarbon and optionally up to 3 heteroatoms selected from O, S, and N;

R¹ and R² are as defined above; and

R⁵ is as defined above, provided that when A is a monocyclic all-carbonring, that R⁵ is other than hydrogen, alkyl, hydroxy substituted alkyl,COC₁ -C₆ alkyl, or unsubstituted or substituted phenyl-(CR⁶ R⁷)_(m) -,when the substituent on the phenyl is alkyl, halo, alkoxy, or NR³ R⁴,and the pharmaceutically acceptable salts and solvates thereof.

A preferred group of compounds provided by the invention have Formula VI##STR8## where X is CH or N, and R¹, R², R³, and R⁴ are as definedabove.

A further preferred group of compounds have Formula VII ##STR9## where Xis CH or N, and R¹ is hydrogen, halo, C₁ -C₆ alkyl, or O--C₁ -C₆ alkyl.

Another preferred group of compounds have the Formula VIII ##STR10##where X, R¹, and R² are as defined above, and R⁵ is C₁ -C₆ alkylsubstituted with 1 or 2 CO₂ R³ groups where R³ is as defined above, andpreferably is hydrogen or alkyl.

A particularly preferred group of compounds are those having acarboxy-substituted alkyl group for R⁵, for example, compounds of theFormula IX ##STR11## where R¹ and R² are as defined above, X is CH or N,and R⁵ is C₁ -C₆ alkyl substituted by 1 or 2 carboxy groups, andoptionally substituted by hydroxy or amino. Especially preferred are thecompounds wherein R⁵ is a residue of an α-amino acid, where the aminogroup of the α-amino acid is part of the isothiazolone ring. Typicalamino acid residues are those from glycine, alanine, valine, leucine,isoleucine, serine, threonine, lysine, δ-hydroxylysine, aspartic acid,glutamic acid, and the like.

Still another preferred group of compounds provided by the invention arepyrimidine derivatives having Formula X ##STR12## where R¹, R², and R⁵are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

"C₁ -C₆ alkyl" means a straight or branched aliphatic group having from1 to 6 carbon atoms. Examples include methyl, ethyl, isobutyl, n-pentyl,and isohexyl.

The term "O--C₁ -C₆ alkyl" means the foregoing alkyl radicals bondedthrough oxygen, examples of which include methoxy, ethoxy, isopropoxy,tert-butoxy, and the like. Typical "C₃ -C₆ cycloalkyl" groups includecyclopropyl, cyclopentyl, cyclohexyl, and the like.

"Het" is a cyclic or bicyclic ring having from 4 to 10 atoms, from oneto four of which are selected from O, S, or N. Het includes non-aromaticgroups such as morpholino and pyrrlidino. Preferred Het groups are 5- or6-membered mono-cyclic aromatic rings having 1 or 2 heteroatoms. Hetincludes bicyclic rings such as benzofuran, isothiazolone, indole, andthe like. Typical groups represented by Het include ##STR13## and thelike. Other typically preferred Het groups include pyrimidine,pyridazine, pyrazine, oxazole, pyrazole, thiazole, and the like.

As noted above, the alkyl, cycloalkyl, phenyl and Het groups which areincluded in the definitions of R¹, R², R³, R⁴, and R⁵ can be substitutedwith 1 to 3 groups selected from halo, hydroxy, NR³ COR⁴, CO₂ R³, NR³R⁴, CONR³ R⁴, S(O)_(m) R³, SO₃ H, S(O)_(m) NR³ R⁴, and COR³, where m,R³, and R⁴ are as defined above. Typical substituted alkyl groups thusinclude chloromethyl, 3-bromopropyl, trifluoromethyl, 4-hydroxyhexyl,1-carboxy-2-methylbutyl, 3-methylthiobutyl, 4-methylsulfonylbutyl,dimethylaminomethyl, 2,3-dibromobutyl, 2-amino-3-chloro-4-carboxybutyl,3-acetomidopropyl, 2-acetylethyl, 2-methoxycarbonylethyl,1,1-diacetylpropyl, and the like.

Preferred substituted alkyl groups are those having 1, 2, or 3substituents selected from halo, hydroxy, and carboxy. Such preferredgroups include 1-bromo-2-hydroxypropyl, 1,1-dimethyl-3-hydroxypropyl,1-hydroxymethyl-2-fluoromethyl-3-carboxybutyl, 1-carboxy-2-methylbutyl,1-carboxy-3-methylbutyl, 1,2,3-trihydroxypentyl, and the like.

Typical substituted cycloalkyl groups include 2-fluorocyclopropyl,2,2-dibromocyclopropyl, 2-carboxycyclobutyl, 2-aminosulfonylcyclopentyl,2-amino-3-carboxycyclopentyl, and 3-isopropylsulfinylcyclohexyl.

In the above formulas, R¹ and R² can be halo, which term includesfluoro, chloro, bromo, and iodo. R¹, R², and R⁵ can include the groupphenyl-(CR⁶ R⁷)_(m) - in which the phenyl can be unsubstituted orsubstituted with halo, hydroxy, NR³ R⁴, NR³ COR⁴, CO₂ R³, CONR³ R⁴,S(O)_(m) R³, S(O)_(m) NR³ R⁴, SO₃ H, and COR³. Typical NR³ R⁴substituents include amino, methylamino, dimethylamino,ethyl-isohexylamino, cyclopropylamino, 3-pyridylamino,N-methyl-2-thienylamino, benzylamino, and 3-chlorobenzylamino.

Typical substituents defined by NR³ COR⁴ includecyclopropylcarbonylamino, N-isobutyl-N-cyclohexyl carbonylamino,acetamido, and the like. Typical groups defined by CO₂ R³ include thefree carboxy acid when R³ is hydrogen, and esters such as C₁ -C₆ alkylesters, benzyl esters, cyclobutyl esters, and the like. Amidesubstituents are defined by CONR³ R⁴, and include carboxamide,N-methyl-carboxamide, and N, N-diethyl-carboxamide. Typical S(O)_(m) R³substituent groups include methylthio, ethylsulfinyl,cyclopropylsulfonyl, and the like. Sulfonamide substituents S(O)_(m) NR³R⁴ include N-methylsulfonamide, N,N-dimethylsulfonamide, and the like.Typical phenyl-(CR⁶ R⁷)_(m) - groups substituted with the foregoingsubstituent groups thus include: ##STR14##

The compounds of the invention can be bicyclic or tricyclic, forexample, when A in Formula I is a monocyclic ring or a bicyclic ring,respectively. The compounds can have from 1 to 3 heteroatoms selectedfrom O, S, and N as part of the A ring system. Typical bicyclic andtricyclic isothiazolones contemplated herein include: ##STR15##

Typical substituted Het(CR⁶ R⁷)_(m) - include: ##STR16##

The compounds to be utilized to treat and prevent retroviral infections,inflammation, and atherosclerosis according to this invention can beprepared by any of several synthetic processes utilizing commonmethodology. For example, an O-halosulfenylbenzoyl halide can be reactedwith an amine according to the following scheme, which is the generalmethod of Fisher and Hurni, Arzneithmittel Forsch., 1964;14:1301:##STR17## where R¹, R², and R⁵ are as defined above, and "halo" includeschloro, bromo, iodo, and the like. Typically, the amine andhalosulfenylbenzoyl halide are employed in approximately equimolarquantities; however, an excess of the amine can be utilized if desired.The reaction generally is substantially complete within about 1 to 8hours when carried out in a mutual solvent such as toluene, ethylenedichloride, or methylene chloride at a temperature of about 0° C. to 45°C. Acid scavengers, such as triethylamine, can be utilized if desired.The product isothiazolone is readily isolated by removing the reactionsolvent, and further purification can be accomplished by crystallizationor chromatography, if desired. The process is equally applicable to allA systems contemplated.

An alternative method of synthesis comprises reacting a 2-unsubstitutedisothiazolone with a compound R₅ L, where L is a leaving group such ashalo. This reaction is depicted as follows: ##STR18## Specific reactionconditions, such as choice of solvents, temperature, molar ratios, acidscavengers, and the like, are similar to the process described above,and are well within the skill of the art.

A preferred method for preparing the isothiazolones comprisesdisproportionation of a 2,2'-dithiobis aryl amide by reaction with anoxidizing agent such as chlorine or bromine according to the followingscheme: ##STR19## where R¹, R², and R⁵ are as defined above. Thisdisproportionation reaction requires starting with a 2,2'-dithio bisarylamide, and these are readily prepared from 2,2'-dithio bisarylcarboxylic acids by reacting the acid with a chlorinating agent such asoxalyl chloride or thionyl chloride to produce the corresponding acidchloride, and then reacting the acid chloride with an amine R⁵ NH₂. Atypical synthesis follows the following scheme: ##STR20##

The 2,2'-dithio-bisaryl carboxylic acids required for the abovesynthesis are well known in the art or are readily prepared by routinemethods. Typical aryl carboxylic acids commonly used include those ofthe following general structures: ##STR21##

The 2,2'-dithio-bisaryl carboxylic acids are readily converted to thecorresponding acid chlorides by reaction with a chlorinating agent suchas thionyl chloride or oxalyl chloride. The reaction can be carried outneat or in an unreactive organic solvent such as dichloromethane,tetrahydrofuran, diethyl ether, dimethylformamide, or the like. Thereaction generally is complete within about 1 to about 8 hours whencarried out at a temperature of about 0° C. to about 100° C. The productacid chlorides are readily isolated simply by removing the reactionsolvent and excess chlorinating agent, for example by evaporation underreduced pressure.

The 2,2'-dithio-bisaryl carboxylic acid chlorides are next converted to2,2'-dithio-bisarylamides by reaction with a primary amine of theformula R⁵ NH₂. Typical primary amines commonly employed include alkylamines and substituted alkyl amines such as methylamine, leucine,isoleucine, serine, threonine, lysine, asparagine, and the like. Anilineand substituted anilines can also be employed, such as 4-hydroxyaniline,3-aminoaniline, 3-methylthioaniline, 4-dimethylsulfamoylaniline, and thelike. The amine and acid chloride generally are mixed in approximatelyequimolar quantities in a mutual solvent such as acetone,dichloromethane, tetrahydrofuran, methanol, and the like. Acidscavengers such as pyridine, triethylamine, N-methylmorpholine, and thelike, can be utilized if desired. The reaction generally is completewithin about 1 to about 18 hours when carried out at a temperature ofabout 0° C. to about 100° C. The 2,2'-dithio-bisaryl amides that areformed are easily isolated by simply removing the reaction solvents andany excess reactants by evaporation under reduced pressure, and furtherpurification generally is not required.

The 2,2'-dithiobisaryl carboxamides can be converted to theisothiazolones of the invention in either of two ways. The carboxamidesreadily react with oxidizing agents such as bromine or chlorine toeffect cyclization to the corresponding isothiazolones. The oxidationgenerally is carried out by mixing an excess of chlorine or bromine withthe carboxamide in a suitable solvent such as a halogenated hydrocarbon,dimethylsulfoxide, dimethylformamide, or the like, typically at areduced temperature of about 0° C. to about 5° C. The productisothiazolone is generally solid at room temperature and normallyprecipitates from the reaction mixture. It can be recovered byfiltration, and further purified, if desired, by routine methods such aswashing, for instance with aqueous sodium bicarbonate or the like, andcrystallized from common solvents such as acetone, ethanol, ethylacetate, and the like.

An alternative method for making the isothiazolones from the2,2'-dithiobis aryl carboxamides comprises first converting thedithiobis intermediate to the corresponding aryl thiol carboxamidederivative, and then cyclizing the thiol and carboxamide to form thefinal product. This scheme is depicted below: ##STR22## The dithiobisintermediates are reacted with a reducing agent such as dithiothreitol(DTT) in a mutual solvent such as dimethylformamide, dimethylsulfoxide,dioxane, and the like. The reduction typically is carried out at atemperature of about 10° C. to about 30° C., and normally is completewithin about 0.5 to about 4 hours. The product aryl thiol carboxamidegenerally is not isolated, other than removing any reaction solvent byevaporation.

The aryl thiol carboxamide can also be prepared from readily available2-hydroxycarboxylic acids according to the following scheme: ##STR23##In this process, a 2-hydroxycarboxylic acid is reacted with an excess ofa common chlorinating agent such as thionyl chloride or phosphoruspentachloride in an unreactive organic solvent such as ethylenedichloride, chloroform, ethyl chloride, toluene, or the like, typicallyat a temperature of about 25° C. to about 60° C. The product, a 2-chloroacid chloride derivative, generally is isolated by simply removing thereaction solvent and excess chlorinating agent, for instance byevaporation under reduced pressure. The chloro acid chloride is thenreacted with a primary amine R⁵ NH₂, in an unreactive organic solventsuch as chloroform, methylene chloride, ethyl chloride, or the like.Typical primary amines commonly employed include natural α-amino acidssuch as glycine, leucine, isoleucine, lysine, aspartic acid, and thelike. Tertiary and aromatic amines such as triethylamine, pyridine, orN-methyl morpholine can be added to act as acid scavenger for thehydrochloric acid that is formed during the reaction. The chlorocarboxamide that is produced is readily isolated by removing thereaction solvent, and further purification can be accomplished byroutine methods such as crystallization, chromatography, and the like.The chloro carboxamide is next reacted with sodium hydrogen sulfide in apolar solvent such as methanol, ethanol, isopropanol, or the like togive the corresponding 2-thiol carboxamide derivative.

The aryl thiol carboxamide is next reacted with an agent to effectcyclization. Typical agents routinely utilized include chlorocarbonylsulfenyl chloride, iodine, bromine, and the like. The cyclization isaccomplished by mixing equimolar quantities of the thiol carboxamide andcyclizing agent in an unreactive organic solvent such as tetrahydrofuranor the like, and stirring the mixture for about 0.5 to about 18 hours ata temperature of about 0° C. to about 30° C. The product isothiozolonetypically precipitates as it is formed, and is readily isolated byfiltration, and further purified, if desired, by crystallization,chromatography, and the like.

Many of the compounds embraced by Formula I can have functionalsubstituent groups (e.g., R¹ and R²) which may need to be derivatized inorder to avoid unwanted side reactions during synthesis. Such functionalsubstituent groups include, for example, hydroxy groups, amino groups,especially primary and secondary amino groups, and carboxylic acidgroups. For example, hydroxy groups, in order to prevent unwanted sidereactions, generally need to be converted to protected hydroxy groupssuch as ethers or esters during chemical reactions at other sites in themolecule. The hydroxy protecting group is subsequently removed toprovide the free hydroxy group. Amino groups and carboxylic acid groupsare similarly derivatized to protect them against unwanted sidereactions. Carboxy groups generally are converted to esters such astert.-butyl ester, benzyl or p-nitrobenzyl ester, and the like. Aminogroups typically are acylated, for example with acetyl chloride or thelike, or silylated with trimethylsilyl or t-butyldimethylsilyl groups.Typical protecting groups, and methods for attaching and cleaving them,are described fully by Greene and Wuts in Protective Groups in OrganicSynthesis, John Wiley and Sons, New York, (2nd Ed; 1991), and McOmie,Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.

Many of the isothiazolones of Formula I are capable of formingpharmaceutically acceptable salts, including acid addition salts andbase salts, as well as solvates, such as hydrates and alcoholates. Allof these pharmaceutical forms are contemplated by this invention and areincluded herein. Acid addition salts are readily formed when a Formula Icompound contains amino substituent groups, or nitrogen atoms arepresent in the A ring system. Base salts can be formed when carboxylicacid substituent groups are present, for example, when R⁵ is a carboxysubstituted alkyl such as carboxymethyl or the like.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphoric, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M., et al., "PharmaceuticalSalts," J. of Pharmaceutical Science, 1977;66:1-19.

The acid addition salts of basic compounds are prepared by contactingthe free base form with a sufficient amount of the desired acid toproduce the salt in the conventional manner. The free base form may beregenerated by contacting the salt form with a base and isolating thefree base in the conventional manner. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but otherwise the salts are equivalentto their respective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine, and procaine (see, for example,Berge S. M., et al., "Pharmaceutical Salts," J. of PharmaceuticalScience, 1977;66:1-19.

The base addition salts of acidic compounds are prepared by contactingthe free acid form with a sufficient amount of the desired base toproduce the salt in the conventional manner. The free acid form may beregenerated by contacting the salt form with an acid and isolating thefree acid in the conventional manner. The free acid forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but otherwise the salts are equivalentto their respective free acid for purposes of the present invention.

Many of the isothiazolones of Formula I contain one or more asymmetriccarbon atoms, and as such, can exist in optically active forms. Forexample, a preferred group of compounds are those wherein R⁵ is aresidue of an α-amino acid such as alanine, valine, leucine, threonine,and the like. Such groups have one or more asymmetric centers. Theracemates can be separated into their respective enantiomers by routinemethodology, including fractional crystallization, high performanceliquid chromatograph, asymmetric synthesis, and the like. The racematesand individual enantiomers are contemplated equally by this invention.

While the forms of the invention herein constitute presently preferredembodiments, many others are possible. It is not intended herein tomention all of the possible equivalent forms or ramifications of theinvention. It is understood that the terms used herein are merelydescriptive rather than limiting, and that various changes may be madewithout departing from the spirit or scope of the invention.

The following detailed examples illustrate specific embodiments of theinvention. The examples are intended to be a general illustration of howto make and use the invention, and are not intended to be limiting inany respect.

Unless otherwise stated, all reagents were obtained from commercialsources. Many of the aryl thiol carboxamides which are utilized asstarting materials are known or are available by the methods described,for example, by Bell, J. Am. Chem. Soc., 1942:2905, Carmellino, et al.,Eur. J. Med. Chem., 1994;29:743-751, Bennett, et al., Organic Prep. andProced. Int., 1974;6(6):287-293 and Vitali, et al., Il Farmaco Ed. Sc.,1968;23:468-476. These references are incorporated herein by referencefor their teaching of synthetic methods for aryl thio carboxamides.

PREPARATION 1

2,2'-Dithiobisbenzoyl chloride

A mixture of 2,2'-dithiobisbenzoic acid (25 g, 81.6 mmol) in 350 mL ofthionyl chloride was heated at reflux for 18 hours. The resultingsolution was cooled and excess thionyl chloride was removed in vacuo.The crude solid was slurried in hexane and the title compound wasrecovered by filtration to yield 21.2 g mp 150°-151° C. This compoundwas used without further purification.

PREPARATION 2

2,2'-Dithiobis[5-fluorobenzoyl chloride]

A mixture of 2,2'-dithiobis[5-fluorobenzoic acid] (5.0 g, 14.6 mmol) andthionyl chloride (40 mL) was reacted according to the proceduredescribed above to yield 4.9 g of 2,2'-dithiobis[5-fluorobenzoylchloride]. This compound was used without further purification.

PREPARATION 3

2,2'-Dithiobis[5-methoxybenzoyl chloride]

A mixture of 2,2'-dithiobis[5-methoxybenzoic acid] (0.8 g, 2.0 mmol) andthionyl chloride (10 mL) was reacted according to the proceduredescribed above to yield 0.8 g of 2,2'-dithiobis[5-methoxybenzoylchloride]. This compound was used without further purification.

PREPARATION 4

2,2'-Dithiobis[5-methylbenzoic acid]

A mixture of 2,2'-dithiobis[5-methylbenzoic acid] (0.6 g, 1.8 mmol) andthionyl chloride (10 ml) was reacted according to the proceduredescribed above to yield 0.3 g of 2,2'-dithiobis[5-methylbenzoylchloride]. The compound was used without further purification.

PREPARATION 5

2,2'-Dithiobis[4-fluorobenzoyl chloride]

A mixture of 2,2'-dithiobis[4-fluorobenzoic acid] (5.0 g, 14.6 mmol) andthionyl chloride was reacted according to the procedure described aboveto yield 4.1 g of 2,2'-dithiobis[4-fluorobenzoyl chloride]. The compoundwas used without further purification.

PREPARATION 6

2,2'-Dithiobis[4-methoxybenzoyl chloride]

A mixture of 2,2'-dithiobis[4-methoxybenzoic acid] (2.2 g, 6.6 mmol) andthionyl chloride (20 mL) was reacted according to the proceduredescribed above to yield 2.1 g of 2,2'-dithiobis[4-methoxybenzoylchloride]. No further purification was required.

PREPARATION 7

2,2'-Dithiobis[4-methylbenzoyl chloride]

A mixture of 2,2'-dithiobis[4-methylbenzoic acid] (3.8 g, 11.9 mmol) andthionyl chloride (50 mL) was reacted according to the proceduredescribed above to yield 3.6 g of 2,2'-dithiobis[4-methylbenzoylchloride]. The compound was used without further purification.

PREPARATION 8

2,2'-Dithiobis[3-pyridinecarbonyl chloride]

A mixture of 2,2'dithiobis[3-pyridinecarboxylic acid (1.5 g, 4.8 mmol)and thionyl chloride (20 mL) was reacted according to the proceduredescribed above to yield 1.3 g of 2,2'-dithiobis[3-pyridinecarbonylchloride]. The compound was used without further purification.

PREPARATION 9

2,2'-Dithiobis[4'-sulfamoylbenzanilide] (general method)

A solution of 2,2'-dithiobisbenzoyl chloride (5.0 g, 14.0 mmol) fromPreparation 1 in 50 mL of dichloromethane was added dropwise to asolution of 4-(aminosulfonyl)-aniline (6.2 g, 36.0 mmol) in 125 mLpyridine cooled to 0° C. The mixture was stirred for 18 hours, and theresulting solid was removed by filtration, washed with 1N HCl, water,and dried in vacuo to yield 7.6 g of crude product. This crude material(6.5 g) was suspended in 50 mL dimethylformamide/60 mL ethanol,filtered, and precipitated from the filtered solution with the additionof 10 mL 4% aqueous NaHCO₃. The product was collected by filtration,washed with ethanol and water to yield 4.3 g of the title compound, mp311°-312° C.

PREPARATION 10

2,2'-Dithiobis[4'-sulfamoyl(4-methoxybenzanilide)]

This compound was prepared according to the general method described inPreparation 9 using 2,2'-dithiobis[4-methoxybenzoyl chloride] (1.1 g,2.7 mmol) in dichloromethane (10 mL) and 4-(aminosulfonyl)-aniline (1.1g, 6.8 mmol) in pyridine (15 mL). The crude product was recrystallizedfrom dimethylformamide, ethanol, and water to yield 0.8 g of the titlecompound.

PREPARATION 11

2,2'-Dithiobis[4'-sulfamoyl(4-methylbenzanilide)]

This compound was prepared according to the general procedure describedin Preparation 9 using 2,2'-dithiobis[4-methylbenzoyl chloride] (2.0 g,5.5 mmol) in dichloromethane (20 mL) and 4-(aminosulfonyl)-aniline (3.4g, 19.9 mmol) in pyridine (40 mL). The crude product was recrystallizedfrom dimethylformamide, ethanol, and water to afford 2.1 g of the titlecompound.

PREPARATION 12

2,2 '- Dithiobis[4'-sulfamoyl(4-fluorobenzanilide)]

This compound was prepared according to the general procedure describedin Preparation 9 using 2,2'-dithiobis[4-fluorobenzoyl chloride] (2.0 g,5.2 mmol) in dichloromethane (20 mL) and 4-(aminosulfonyl)-aniline (2.2g, 13.0 mmol) in pyridine (30 mL). The crude product was recrystallizedfrom dimethylformamide, ethanol, and water to yield 2.6 g of the titlecompound.

PREPARATION 13

2,2'-Dithiobis[4'-sulfamoyl (5-methylbenzanilide)]

This compound was prepared according to the general method ofPreparation 9 using 2,2'-dithiobis[5-methylbenzoyl chloride] (2.0 g, 5.3mmol) in dichloromethane (20 mL) and 4-(aminosulfonyl)-aniline (2.3 g,13.3 mmol) in pyridine (30 mL). The crude product was recrystallizedfrom dimethylformamide, ethanol, and water to yield 1.8 g of the titlecompound.

PREPARATION 14

[S-(R*,R*)]-2-[2-[2-(1-tert-Butoxycarbonyl-3-methylbutylcarbamoyl)-5-methoxy-phenyldisulfanyl]-4-methoxybenzoylamino]-4-methyl-pentanoicacid tert-butyl ester (general method)

A solution of 2,2'-dithiobis[4-methoxybenzoyl chloride] (1.1 g, 2.7mmol) from Preparation 9 in 10 mL of dichloromethane was added dropwiseto a solution of L-leucine,t-butyl ester, monohydrochloride (1.5 g, 6.8mmol) and N-methyl morpholine (1.6 mL, 14.0 mmol) in 25 mLdichloromethane cooled to 0° C. to 5° C. The resulting solution wasstirred for 18 hours, and then warmed to ambient temperature (25° C.).The mixture was extracted with 0.5N HCl, water, 8% aqueous NaHCO³, andbrine. The organic layer was dried with MgSO₄, filtered, andconcentrated in vacuo. The crude product was recrystallized from ethylacetate to yield 1.2 g of the title compound.

PREPARATION 15

[S-(RR*)-2-[2-[2-(1-tert-Butoxycarbonyl-3-methylbutylcarbamoyl)-4-fluoro-phenyldisulfanyl]-5-fluorobenzoylamino]-4-methyl-pentanoicacid tert-butyl ester

This compound was prepared according to the general method ofPreparation 14 using 2,2'-dithiobis[5-fluorobenzoyl chloride] (2.0 g,5.2 mmol) in 20 mL dichloromethane, L-leucine,t-butyl ester,monohydrochloride (2.5 g, 11.4 mmol), and N-methyl morpholine (1.4 mL,12.5 mmol) in 30 mL dichloromethane. The crude product wasrecrystallized from ethyl acetate to yield 1.8 g of the title compound.

PREPARATION 16

[S-(R*,R*)]-2-[2-[2-(1-tert-Butoxycarbonyl-3-methylbutylcarbamoyl)-5-methyl-phenyldisulfanyl]-4-methylbenzoylamino]-4-methyl-pentanoicacid tert-butyl ester

This compound was prepared according to the general method described inPreparation 14 using 2,2'-dithiobis[4-methylbenzoyl chloride] (1.8 g,7.8 mmol) in 20 mL dichloromethane, L-leucine,t-butyl ester,monohydrochloride (4.0 g, 17.9 mmol), and N-methyl morpholine (4.6 mL,41 mmol) in 60 mL dichloromethane. The crude product was recrystallizedfrom ethyl acetate to yield 1.9 g of the title compound.

PREPARATION 17

[S-(R*,R*)]-2-[[2-[3-(1-tert-Butoxycarbonyl-3-methylbutylcarbamoyl)-pyridin-2-yldisulfanyl]-pyridine-3-carbonyl]-amino]-4-methyl-pentanoicacid tert-butyl ester

This compound was prepared according to the general method described inPreparation 14 using 2,2'-dithiobis[3-pyridinecarbonyl chloride] (0.8 g,2.1 mmol) in 10 mL dichloromethane and L-leucine, t-butyl ester,monohydrochloride (1.5 g, 5.7 mmol) in 20 mL pyridine. The crude productwas recrystallized from ethyl acetate to yield 1.9 g of the titlecompound.

PREPARATION 18

[S-(R*,R*)]-2-[2-[2-(1-Carboxy-2-methylbutylcarbamoyl)phenyldisulfanyl]-benzoylamino]-3-methylpentanoic acid tert-butyl ester

A solution of 10.0 g (53.2 mmol) of L-isoleucine t-butyl ester in 100 mLof dichloromethane was mixed with 5.6 g (55.0 mmol) ofN-methylmorpholine. The resulting solution was cooled to 0° C. andreacted by rapid dropwise addition of a solution of 8.3 g (24.2 mmol) of2,2'-dithiobisbenzoyl chloride (from Preparation 1) in 100 mL ofdichloromethane, keeping the temperature below 0° C. The mixture wasstirred at 0° C. for 1 hour and then stirred at room temperature for 18hours. The solid which had formed was removed by filtration, washed withwater, and dried in vacuo to give 6.5 g of the title compound. Thefiltrate was washed with water, 0.5M hydrochloric acid, water, dried(MgSO₄), filtered, and evaporated in vacuo to give an additional 6.9 gof the title compound having comparable purity.

PREPARATION 19

[S-(R*,R*)]-2-[2-[2-(1-Carboxy-2-methylbutylcarbamoyl)-phenyldisulfanylbenzoylamino]-3-methylpentanoicacid

A solution of 13.2 g (20.5 mmol) of the tert-butyl ester (fromPreparation 18) in 50 mL of trifluoroacetic acid was stirred at roomtemperature for 18 hours. The solvent was removed in vacuo, and theresidue was dissolved in 50 mL of dichloromethane. The dichloromethanewas removed in vacuo, and the residue was triturated with 150 mL ofdiethyl ether/pentane (2:1 v/v), and the resulting solid was removed byfiltration. After washing with 50 mL of diethyl ether/pentane (2:1) andthen with pentane, the solid was dried in vacuo and identified as 9.9 gof the title compound, mp 211°-213° C.

PREPARATION 20

[S-(R*,R*)]-2-[2-[2-(1-Carboxy-3-methylbutylcarbamoyl)-5-methoxy-phenyldisulfanyl]-4-methoxybenzoylamino]-4-methyl-pentanoicacid (general method)

A solution of[S-(R*,R*)-2[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methoxyphenyldisulfanyl]-4-methoxybenzoylamino]-4-methyl-pentanoicacid tert-butyl ester (1.2 g, 1.7 mmol) and anisole (1 mL) in 10 mLdichloromethane, cooled to about 0° C., was treated dropwise with 10 mLof trifluoroacetic acid. The mixture was allowed to warm to ambienttemperature. After 4 hours, 5 mL toluene was added, and the solventswere removed in vacuo. The crude product was recrystallized frommethanol/water to yield 0.7 g of the title compound.

PREPARATION 21

[S-(R*,R*)]-2-[2-[2-(1-Carboxy-3-methylbutylcarbamoyl)-4-fluorophenyldisulfanyl]-5-flourobenzoylamino]-4-methyl-pentanoicacid

The general method of Preparation 20 was followed using[S-(R*,R*)]-2-[2-[[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino]-4-methylpentanoic acid tert-butyl ester (1.8 g, 2.6 mmol) in 20 mLdichloromethane, anisole (2 mL), and 20 mL trifluoroacetic acid. Thecrude product was recrystallized from methanol/water to afford 0.9 g ofthe title compound.

PREPARATION 22

[S-(R*,R*)]-2-[2-[-(1-Carboxy-3-methyl-butylcarbamoyl)-5-methylphenyldisulfanyl]-4-methylbenzoylamino]-4-methyl-pentanoicacid

The general method of Preparation 20 was followed using[S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methyl-phenyldisulfanyl]-4-methyl-benzoylamino]-4-methyl-pentanoicacid tert-butyl ester (1.9 g, 2.8 mmol) in 20 mL dichloromethane,anisole (2.0 mL), and 10 mL trifluoroacetic acid. The crude product wasrecrystallized from methanol/water to yield 1.1 g of the title compound.

PREPARATION 23

[{S-(R*,R*)]-2-[[2-[3-(1-Carboxy-3-methylbutylcarbamoyl)-pyridin-2-yl-disulfanyl]-pyridine-3-carbonyl]-amino]-4-methyl-pentanoicacid

The general method of Preparation 20 was followed using[S-(R*,R*)]-2-([2-[3-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-pyridin-2-yldisulfanyl]-pyridine-3-carbonyl]-amino)-4-methyl-pentanoicacid tert-butyl ester (1.9 g, 2.9 mmol) in 20 mL dichloromethane,anisole (1.5 mL), and 10 mL trifluoroacetic acid. The crude product wasrecrystallized from methanol/water to yield 1.2 g of the title compound.

PREPARATION 24

2-Chloro-5-nitrobenzamide

A mixture of 2-chloro-5-nitrobenzoic acid (15.0 g, 74.0 mmol) and 200 mLof dichloromethane was reacted with oxalyl chloride (16.2 mL, 186.0mmol) and a catalytic amount of dimethylformamide. The mixture wasstirred at 25° C. for 3 hours. The solvent was removed in vacuo, and theresidue was redissolved in 200 mL of dichloromethane. The solution wascooled to 0° C., and ammonia was bubbled through the cold solution for 5minutes, whereupon the product precipitated to form solution. Theproduct was collected by filtration to yield 6.8 g, mp 174°-175° C.

PREPARATION 25

2,2'-Dithiobis(5-nitrobenzamide)

To a refluxing solution of 2-chloro-5-nitrobenzamide (6.8 g, 33.0 mmol)from Preparation 24 in 90 mL of ethanol was added portion-wise sodiumsulfide hydrate, Na₂ S(9H₂ O) (2.6 g, 20.5 mmol) and sulfur (0.7 g, 20.5mmol). The mixture was heated at reflux for 1 hour, then cooled to roomtemperature, whereupon a solid formed. The solid was collected byfiltration to yield 2.6 g of the title compound, mp 266°-269° C.

PREPARATION 26

2,2'-Dithiobis(5-aminobenzamide)

2,2'-Dithiobis(5-nitrobenzamide) (2.6 g, 7.0 mmol) was addedportion-wise to a refluxing slurry of reduced iron (8.7 g) in 65 mL ofwater containing 0.1 mL of acetic acid. The resulting slurry was heatedat reflux for 2.0 hours, then cooled to room temperature. The slurry wasmade strongly basic (pH 11) by the addition of 14 mL of 1N NaOH. Thealkaline mixture was filtered, and acetic acid was added to the solutionto adjust the pH to 7.0. While bubbling oxygen into the solution, apH=6-7 was maintained with the addition of acetic acid. A solidgradually formed as the pH begins to stabilize. The product (1.1 g) wasrecovered by filtration, mp 188°-190° C.

PREPARATION 27

2,2'-Dithiobis(5-acetylamino)benzamide

2,2'-Dithiobis(5-aminobenzamide) (1.1 g, 3.4 mmol) was dissolved in 6 mLof glacial acetic acid on a steam bath and reacted with acetic anhydride(0.7 mL, 7.2 mmol). Upon cooling, the product precipitated fromsolution. An additional 4 mL of glacial acetic acid and 0.1 mL of aceticanhydride was added, and the mixture was heated at reflux for 30minutes, and then cooled to room temperature. The crude product wasrecovered by filtration and recrystallized fromdimethylformamide/dimethyl sulfoxide/water to yield 0.8 g of the titleproduct, mp 301°-303° C.

PREPARATION 28

2,2'-Dithiobis[N-[4-[(acetylamino)sulfonyl]phenyl] benzamide]

The compound was prepared according to the general method of Preparation9 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.0 mmol) in 30 mL ofdichloromethane and 4-[(acetylamino)sulfonyl]aniline (5.6 g, 26.0 mmol)in 100 mL of pyridine. The crude product was purified on a silica gelcolumn using chloroform/methanol (1:1 v/v) as the mobile phase. The purefractions were pooled, concentrated in vacuo, and the solid wascrystallized from ethanol/water (1:1 v/v) to yield 0.5 g of the titlecompound, mp 180°-182° C.

PREPARATION 29

2-Mercapto-N-(4-sulfamoylphenyl)benzamide

2,2'-Dithiobis[4'-sulfamoylbenzanilide] (0.1 g, 0.2 mmol) was dissolvedin 4 mL of dimethylformamide and 1.6 mL of 2.7% aqueous NaH₂ PO₄.Dithiothreitol (0.1 g, 0.7 mmol) was added, and the mixture was stirredat 25° C. for 0.5 hours. Formic acid (10 mL 10% aqueous) was added toprecipitate the product, which was collected by filtration, washed withwater, and with diethyl ether to yield 72 mg of the title compound, mp230°-231° C.

PREPARATION 30

2-[2-[2-(Carboxymethylcarbamoyl)-phenyldisulfanyl]benzoylamino]aceticacid

To 18 g (0.24 mol) of glycine in 75 mL of absolute ethanol was added 100mL of a sodium ethoxide solution prepared from dissolution of 4.6 g (0.2mol) of sodium. The mixture was cooled to -60° C. and 17.2 g (0.05 mol)of 2,2'-dithiobisbenzoyl chloride was added portionwise. The mixture wasbrought to room temperature and stirred overnight. The solids wereremoved by filtration, and the filtrate was acidified with 2N HCl.Solids were collected, dissolved in sodium bicarbonate solution, and thesolution filtered. The filtrate was acidified with HCl and the solidscollected and dried at 110° C. for 24 hours to give 6.8 g of the titlecompound, mp 13°-215° C.

PREPARATION 31

2-[2-[2-(1-Carboxy-2-methylpropylcarbamoyl)phenyldisulfanyl]benzoylamino]-3-methylbutanoic acid

Using the method employed in Preparation 30, 17.8 g (0.15 mol) of D,Lvaline was reacted with 17.2 g (0.05 mol) of 2,2'-dithiobisbenzoylchloride to produce 11.4 g of the title compound after recrystallizationfrom acetic acid, mp 226.5°-227.5° C.

PREPARATION 32

4-[2-[2-(3-Carboxypropylcarbamoyl)phenyldisulfanyl] benzoylamino]butanoic acid

Following the procedure in Preparation 30, 16 g (0.15 mol) of4-amino-butanoic acid was reacted with 10.8 g (0.03 mol) of2,2'-dithiobisbenzoyl chloride to afford 7.14 g of the title compound.

PREPARATION 33

8-Chloro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid(2-pyridin-2-yl-ethyl)-amide

To 23.3 g (0.10 mol) of 8-hydroxy-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (J. Med, Chem., 1968;11:160) in 500mL of ethylene chloride was added 35 mL (0.47 mol) of thionyl chlorideand 1 mL of DMF. The mixture was heated at reflux overnight,concentrated to 100 mL, and the solids collected to give 18.7 g of8-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbonyl chloride, which wasused without purification. To 13.5 g (˜0.05 mol) of this material in1000 mL of ethylene chloride was added 10 mL (0.07 mol) of triethylamineand the mixture cooled to 15° C. To this mixture was added 6.25 g (0.51mol) of 2-(2-aminoethyl)pyridine and the mixture was stirred for 24hours at room temperature. The reaction was quenched by addition of 500mL H₂ O. The organic layer was washed with water, dried (MgSO₄), andconcentrated to give 16 g of the title compound, mp 145°-146° C.

PREPARATION 34

8-Mercapto-[1,3]dioxolo[4,5 g]quinoline-7-carboxylic acid(2-pyridin-2-yl-ethyl)-amide

To 10.4 g (0.025 mol) of 8-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (2-pyridin-2yl-ethyl)-amide in 100 mLof ethanol was added 7.2 g (0.1 mol) of sodium hydrogensulfide and themixture was heated at reflux for 3 hours. The mixture was cooled and thesolids filtered, washed with ethanol, and then with water. The filtratewas concentrated and the solids were suspended in water, collected byfiltration, and recrystallized from ethanol to give 6.8 g of the titlecompound, mp 258°-260° C.

PREPARATION 35

4-Chloro-2-phenyl-pyrimidine-5-carboxylic acid(2-diethylamino-ethyl)-amide

Using the procedure of Preparation 33, 15.5 g (0.072 mol) of4-hydroxy-2-phenyl-pyrimidine-5-carboxylic acid (J. Med. Chem.,1964;7:68) was reacted with 8.5 g (0.073 mol) of2-diethylaminoethylamine to give 18 g of the title compound afterrecrystallization from benzene, mp 40°-45° C.

PREPARATION 36

4-Mercapto-2-phenyl-pyrimidine-5-carboxylic acid(2-diethylamino-ethyl)-amide

Using the procedure in Preparation 34, 6.4 g (0.02 mol) of4-chloro-2-phenyl-pyrimidine-5-carboxylic acid(2-diethylamino-ethyl)-amide was reacted with 4.8 g (0.066 mol) ofsodium hydrogen sulfide to afford 4.2 g of the title compound, mp178°-180° C.

PREPARATION 37

5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid(2-pyridine-2-yl-ethyl)-amide

Using the procedure in Preparation 33, 28.4 g (0.13 mol) of5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid was reactedwith 15.9 g (0.13 mol) of 2-(2-aminoethyl) pyridine to produce the titlecompound, which was used without purification.

PREPARATION 38

5-Mercapto-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid(2-pyridin-2-yl-ethyl) amide

Using the procedure of Preparation 34, 29.3 g (0.087 mol) of5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-caboxyclic acid(2-pyridin-2-yl-ethyl)-amide was reacted with 19.3 g (0.27 mol) sodiumhydrogen sulfide in cellosolve to give 24.0 g of the title compound,which was used in Example 22 without purification.

PREPARATION 39

4-Chloro-2-dimethylamino-pyrimidine-5-carboxylic acid benzylamide

Using the procedure of Preparation 33, 61.6 g (0.337 mol) of2-dimethylamino-4-hydroxy-pyrimidine-5-carboxylic acid was reacted with37 g (0.34 mol) of 2-aminomethyl pyridine to afford 14.3 g of the titlecompound, which was used without purification.

PREPARATION 40

2-Dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid benzylamide

Using the procedure of Preparation 34, 14.3 g (0.045 mol) of4-chloro-2-dimethylamino-pyrimidine-5-carboxylic acid benzylamide and 12g (0.21 mol) of sodium hydrogen sulfide were reacted to give 5.7 g ofthe title compound, mp 175°-178° C.

PREPARATION 41

4-Chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide

Using the procedure of Preparation 33, 31.0 g (0.143 mol) of4-hydroxy-2-phenyl-pyrimidine-5-carboxylic acid and 60 mL (0.82 mol) ofthionyl chloride were reacted to give 37.8 g of crude chloro acidchloride. A 5.0 g (19.8 mmol) portion of the acid chloride was reactedwith 2.12 g (19.8 mmol) of benzylamine to give 6.27 g of the titlecompound, which was used without purification.

PREPARATION 42

4-Mercapto-2-phenyl-pyrimidine-5-carboxylic acid benzylamide

Using the procedure from Preparation 34, 5.8 g (17.9 mmol) of4-chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide was reactedwith 5.1 g (72 mmol) of sodium hydrogen sulfide to give 3.75 g of thetitle compound, mp 189°-193° C.

EXAMPLE 1

4-(3-Oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide

To a solution of 60 mL of methanol and 60 mL of tetrahydrofuran cooledto 0° C. was added dropwise 3.9 g (30.0 mmol) of chlorocarbonylsulfenylchloride. The mixture was stirred at 0° C. for 20 minutes and thendiluted by addition of 9.0 g (29.2 mmol) of2-thio-N-(4-sulfamoylphenyl)benzamide. The reaction mixture was stirredat 0° C. for 0.5 hours, warmed to room temperature, and stirred for 18hours. The suspension was diluted with 200 mL of diethyl ether, stirredfor 1 hour, and the solid was removed by filtration. After washing withfresh diethyl ether, the solid was dried in vacuo to give 7.8 g of thetitle compound. An additional 2.2 g was obtained by concentrating themother liquors and triturating the residue with diethyl ether. The mp ofboth fractions was 283°-285° C.

EXAMPLE 2

[S-(R*,R*)]-3-Methyl-2-(3-oxo-3h-benzo[d]isothiazol-2-yl)pentanoic acid

To a stirred suspension of 5.3 g (10.0 mmol) of[S-(R*,R*)]-2-[2-[2-(1-carboxy-2-methylbutylcarbamoyl)phenyldisulfanylbenzoylamino]-3-methylpentanoic acid (from Preparation19) in 200 mL of dichloromethane was added dropwise 2.4 g (15.0 mmol) ofliquid bromine. The reaction mixture was stirred at room temperature for2 hours and concentrated to dryness in vacuo. The residue was trituratedwith dichloromethane. The dichloromethane was removed by evaporation invacuo to remove excess bromine. The residue was partitioned betweendichloromethane/5% aqueous sodium bicarbonate (200 mL each). The aqueouslayer was separated, washed with fresh dichloromethane, and acidified topH 1.5 with 6.0M hydrochloric acid. The acidic aqueous solution wasextracted with dichloromethane (2×75 mL). The organic layers werecombined, washed with water, dried (MgSO₄), filtered and concentrated todryness in vacuo to give 4.8 g of the title compound, mp 50°-52° C.

EXAMPLE 3

N-Acetyl-4-(3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide/(general method)

A solution of2,2'-dithiobis-N-[4-[[acetylamino]sulfonyl]phenyl]benzamide (1.0 g, 1.5mmol) in 1 mL dimethylformamide was diluted with 20 mL dichloromethane,whereupon a fine precipitate formed. Bromine (0.3 g, 1.8 mmol) in 5 mLdichloromethane was added dropwise to the mixture. A homogenous solutiongradually formed, and then a solid reformed. The solid was collected byfiltration and recrystallized from acetic acid/water (1:1 v/v) to afford0.6 g of the title compound, mp 254°-255° C.

EXAMPLE 4

N-(3-Oxo-2,3-dihydro-benzo[d]isothiazol-5-yl)-acetamide

Following the general method of Example 3, a slurry of2,2'-dithiobis[5-acetylamino]benzamide (2.0 g, 4.8 mmol) in 4 mLdimethyl sulfoxide and 20 mL dichloromethane was reacted with bromine(0.8 g, 5.0 mmol) in 10 mL of dichloromethane. The solid product wascollected by filtration and recrystallized from 5 mL of hot acetic acidto yield 0.8 g of the title compound.

EXAMPLE 5

4-(5-Methoxy-3-oxo-3h -benz[d]isothiazol-2-yl)-benzenesulfonamide

Following the general method of Example 3, a slurry of 2,2'-dithiobis(4-sulfamoyl (5-methoxybenzanilide)) (0.8 g, 1.2 mmol) in 2 mLdimethylformamide and 20 mL dichloromethane was reacted with bromine(0.2 g, 1.3 mmol) in 10 mL dichloromethane. The crude product wasrecrystallized from methanol/water to afford 0.2 g of the titlecompound.

EXAMPLE 6

4-(6-Methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide

Following the general method of Example 3, a slurry of2,2'-dithiobis[4'-sulfamoyl(4-methylbenz anilide)] (2.1 g, 3.2 mmol)(from Preparation 11) in 4 mL dimethylformamide/40 mL dichloromethanewas reacted with bromine (0.6 g, 3.6 mmol) in 15 mL dichloromethane. Thecrude product was recrystallized from dimethylformamide/water to yield0.9 g of the title compound.

EXAMPLE 7

4-(6-Fluoro-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide

Following the general method of Example 3, a slurry of2,2'-dithiobis[4'-sulfamoyl(4-fluorobenz anilide)] (1.8 g, 2.7 mmol)(from Preparation 12) in 4 mL dimethylformamide and 30 mLdichloromethane was reacted with bromine (0.5 g, 3.2 mmol) in 20 mL ofdichloromethane. The crude product was recrystallized fromdimethylformamide/water to yield 1.1 g of the title compound, mp265°-266° C.

EXAMPLE 8

4-(5-Methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide

Following the general method of Example 3, a slurry of2,2'-dithiobis[4'-sulfamoyl(5-methylbenzanilde)] (1.1 g, 1.7 mmol) (fromPreparation 13) in 2 mL dimethylformamide and 20 mL dichloromethane wastreated with bromine (0.3 g, 1.9 mmol) in 10 mL dichloromethane. Thecrude compound was recrystallized from dimethylformamide/water to afford0.4 g of the title compound.

EXAMPLE 9

(S)-4-Methyl-2-(6-methoxy-3-oxo-3h-benzo[d]isothiazol-2-yl)-pentanoicacid

Following the general method of Example 3, a slurry of{[s-(R*,R*)]-2-[2-[2-(1-carboxy-3-methylbutylcarbamoyl)-5-methoxyphenyldisulfanyl]-4-methoxybenzoylamino}]-4-methyl-pentanoicacid (1.4 g, 2.3 mmol) (from Preparation 20) in 4 mL of acetonitrile and10 mL dichloromethane was treated with bromine (0.4 g, 2.6 mmol) in 10mL dichloromethane. The crude product was recrystallized frommethanol/water to afford 0.8 g of the title compound.

EXAMPLE 10

(S)-4-Methyl-2-(5-fluoro-3-oxo-3h-benzo[d]isothiazol-2-yl)-pentanoicacid

Following the general method of Example 3, a slurry of{s-(R*,R*)]-2-{-[2-(1-carboxy-3-methylbutylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino}-4-methyl-pentanoicacid (2.1 g, 3.6 mmol) (from Preparation 21) in 8 mL acetonitrile and 25mL dichloromethane was treated with bromine (0.7 g, 4.4 mmol) in 15 mLdichloromethane. The crude compound was recrystallized frommethanol/water to afford 1.4 g of the title compound, mp 161°-162° C.

EXAMPLE 11

(S)-4-Methyl-2-(6-methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-pentanoicacid

Following the general method of Example 3, a slurry of[s-(R*,R*)]-2-[-[2-(1-carboxy-3-methylbutylcarbamoyl)-4-methylphenyldisulfanyl]-5-methylbenzoylamino]-4-methyl-pentanoicacid (1.8 g, 3.2 mmol) (from Preparation 22) in 5 mL acetonitrile and 20mL dichloromethane was reacted with bromine (0.6 g, 3.7 mmol) in 10 mLdichloromethane. The crude product was recrystallized frommethanol/water to afford 1.3 g of the title compound.

EXAMPLE 12

(S)-4-Methyl-2-(3-oxo-3h-isothiazolo[5.4-b] pyridin-2-yl)-pentanoic acid

Following the general method of Example 3, a slurry of{[S-(R*,R*)]-2-(2-[3-(1-carboxy-3-methylbutylcarbamoyl)-pyridin-2-yl-disulfanyl]-pyridine-3-carbonyl}-amino)-4-methyl-pentanoicacid (2.1 g, 4.1 mmol) (from Preparation 23) in 3 mL acetonitrile and 10mL dichloromethane was reacted with bromine (0.3 g, 1.8 mmol) in 8 mLdichloromethane. The crude compound was recrystallized frommethanol/water to yield 0.3 g of the title compound.

EXAMPLE 13

2-(3-Oxo-3h-benzo[d]isothiazol-2-yl) acetic acid

To 6.0 g (13.3 mmol) of 2-[2-[2-carboxylmethyl carbamoyl]phenyldisulfanyl]benzoylamino] acetic acid (from Preparation 30)suspended in 50 mL of CCl₄ was added dropwise 0.83 mL (16.1 mmol) ofbromine in 15 mL of CCl₄ over 1 hour. The solids were removed byfiltration. A 6.0 g portion was heated at reflux in 25 mL of acetic acidfor 1 hour. The mixture was cooled, and the solids were collected byfiltration. Recrystallization from 90% methyl cellosolve, followed bydrying at 50° for 24 hours gave 3.0 g of the title compound, mp236°-238° C.

EXAMPLE 14

3-Methyl-2-(3-oxo-3h-benzo[d]isothiazol-2-yl)-butanoic acid

Following the procedure of Example 13, 6.0 g (13.6 mol) of2-[2-[2-(1-carboxy-3-methylbutylcarbamoyl)phenyldisulfanyl]benzoylamino]-3-methylbutanoic acid wasreacted with bromine to provide 2.25 g of the title compound, mp166°-168° C.

EXAMPLE 15

2-Phenyl-3-oxo-3h-benz[d]isothiazole

Using the procedure from Example 13, 20 g (43.7 mmol) of2,2'-dithiobisbenzanilide (prepared as described in J Med. Chem.,1985;28:1772) was reacted with bromine to give 10.55 g of crudeisothiazole. Crystallization from absolute ethanol, and then isopropanolgave 5.4 g of 3-phenyl-3-oxo-3h-benz[d]isothiazole, mp 143°-145° C.

EXAMPLE 16

2-(4-Acetylphenyl)-3-oxo-3h-benz[d]isothiazole

To 7.0 g (12.9 mmol) of 2,2'-dithiobis[4'48 -acetyl (benzanilide)] in 50mL of CCl₄ was added dropwise over 1 hour a solution of 0.7 mL (13.5mmol) of bromine in 5 mL of CCl₄. The solid precipitate was collected byfiltration. A 1.3 g portion of the solid was slurried in sodiumbicarbonate solution for 30 minutes. The solid was collected byfiltration and dried at 70° C. for 24 hours to give 0.87 g of the titlecompound, mp 183°-185° C.

EXAMPLE 17

4-(3-Oxo-2-h-benzo[d]isothiaz-2-yl) butanoic acid

Using the procedure from Example 13, 2.4 g (5.0 mmol) of4-[2-[2-(3-carboxypropylcarbamoyl) phenyldisulfanyl]benzoylamino]butanoic acid (from Preparation 32) was reacted with bromine to give0.85 g of the crude isothiazolone, which was recrystallized fromisopropanol to give 0.76 g of the title compound, mp 97°-99° C.

EXAMPLE 18

2-(4-Methylpyridin-2-yl)-3-oxo-3h-benzo[d]isothiazole

Using the method of Fischer and Hurni (Arzneimittel Forsch.,1964;14:1301) 5.4 g (0.05 mol) of 2-amino-4-methylpyridine in 50 mL ofpyridine at 10° C. was reacted with 10.3 g (0.05 mol) of2-chlorosulfenylbenzoyl chloride. The mixture was heated to 50° C. andmaintained at that temperature for 2 hours. The mixture was cooled to25° C. and filtered. The solid was recrystallized from benzene to give4.5 g of the title compound, mp 195°-196.5° C.

EXAMPLE 19

4-(3-Oxo-3h-benzo[d]isothiazol-2-yl) phenylacetic acid

To a mixture of 7.55 g (0.05 mol) of 4-aminophenylacetic acid and 15.15g (0.15 mol) of triethylamine in 25 mL of ethyl cellosolve was added10.3 g (0.05 mol) of 2-chlorosulfenylbenzoyl chloride (ArzneimittelForsch., 1964;14:1301) . The mixture was stirred at room temperature for3 hours, concentrated in vacuo, and water was added to the residue. Themixture was acidified with HCl and filtered to give 9.9 g of the titlecompound, mp 173°-175° C.

EXAMPLE 20

2-[2-(2-Pyridinyl)ethyl]-[1,3]dioxolo[4.5-g]isothiazolo[4,5-c]quinolin-3(2H)-one

To 4.1 g (0.012 mol) of 8-mercapto-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (2-pyridin-2-yl-ethyl)-amide (fromPreparation 34) and 5 mL (0.035 mol) of triethylamine in 750 mL ofmethanol was added 2.95 g (0.012 mol) of iodine in 100 mL of methanol.The mixture was heated at reflux for 2 hours, cooled, and thenconcentrated to an oil. The residue was slurried in water, and the solidwas collected and recrystallized in ethanol to give 3.5 g of the titlecompound, mp 200°-201° C.

EXAMPLE 21

2-[2-(Diethylamino)ethyl]-6-phenyl-isothiazolo[5,4-d]pyrimidin-3(2H)-one

Using the procedure of Example 20, 3.3 g (0.01 mol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid(2-diethylamino-ethyl)-amide (from Preparation 36) and 2.54 g (0.01 mol)of iodine were reacted to give 2.25 g of the title compound afterrecrystallization from isopropanol, mp 106°-107° C.

EXAMPLE 22

3-Methyl-1-phenyl-5-[2-(2-pyridinyl)ethyl]-1H-pyrazolo[4,5-d]isothiazol-4(5H)-one

Using the procedure of Example 20, 24 g (0.069 mol) of5-mercapto-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid(2-pyridin-2-yl-ethyl)amide (from Preparation 38) was reacted with 17.6g (0.069 mol) of iodine to give 4.8 g of the title compound after tworecrystallizations from isopropanol, mp 137°-138° C.

EXAMPLE 23

6-(Dimethylamino)-2-(2-pyridinylmethyl)isothiazolo[5,4-d]pyrimidin-3-(2H)-one

Using the procedure of Example 20, 5.7 g (0.02 mol) of2-dimethylamino-4-mercapto pyrimidine-5-carboxylic acid benzylamide(from Preparation 40) was reacted with 5.0 g (0.02 mol) of iodine togive 2.27 g of the title compound after crystallization from ethanol, mp145°-146° C.

EXAMPLE 24

2-Benzyl-6-phenyl-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 2.0 g (6.22 mmol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid benzylamide (fromPreparation 42) was reacted with 1.74 g (6.8 mmol) of iodine to give1.74 g of the title compound after crystallization from isopropanol, mp166°-167° C.

EXAMPLE 25

4-(3-Oxo-3h-benz-[d]isothiazol-2-yl)-phenyl acetic acid

Using the procedure of Example 13, 1.5 g (2.6 mmol) of4-[2-[2-(4-carboxymethylphenylcarbamoyl) phenyldisulfanyl]benzoylamino]phenylacetic acid was reacted with bromine to give 0.62 g of the titlecompound, mp 173°-175° C.

EXAMPLE 26

(S)-2,6-Bis-(3-oxo-3H-benzo[d]isothiazol-2-yl)-hexanoic acid methylester

Using the procedure from Example 18, 0.77 g (3.3 mmol) of lysine methylester dihydrochloride and 2.1 mL (15 mmol) of triethylamine in 60 mL ofdichloromethane was reacted with 1 g (3.0 mmol) of2-chlorosulfenylbenzoyl chloride. The mixture was stirred at roomtemperature for 18 hours, then the solution was washed with 1N HCl,saturated NaHCO₃, and brine. The solution was dried and concentrated togive 1 g of an oil. The compound was purified by chromatography (SiO₂,CHCl₃ -CHCl₃ /MEOH; 98/2) to give 0.16 g of the title compound as aglass. NMR (DMSO): δ 8.03 (m, 2H), 7.61 (m, 2H), 7.50 (m, 2H), 7.41 (m,2H), 5.42 (m, 1H), 3.88 (t, 2H), 3.75 (s, 3H), 2.24 (m, 1H, 2.11 (m, 1H,1.87 (m, 2H), 1.44 (m, 2H).

EXAMPLE 27

2-(2-Morpholin-4-yl-ethyl)-6-phenyl-isothiazolo[5,4-d) pyrimidin-3-one

Using the procedure of Example 20, 2.0 g (5.81 mmol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid(2-morpholin-4-yl-ethyl)-amide were treated with 1.47 g (5.81 mmol) ofiodine to give 1.21 g of the title compound after recrystallization fromisopropanol, mp 163°-165° C.

EXAMPLE 28

2-Phenethyl-6-phenyl-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 2.0 g (5.96 mmol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid phenethyl-amide weretreated with 1.66 g (6.56 mmol) of iodine to give 1.42 g of the titlecompound after recrystallization from isopropanol, mp 144°-147° C.

EXAMPLE 29

6-phenyl-2-pyridin-2-ylmethyl-isothiazolo[5,4-d] pyrimidin-3-one

Using the procedure of Example 20, 2.0 g (6.20 mmol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid(pyridin-2-ylmethyl)-amide were treated with 1.73 g (6.82 mmol) ofiodine to give 1.62 g of the title compound after recrystallization fromisopropanol, mp 154°-156° C.

EXAMPLE 30

6-phenyl-2-(2-pyridin-2-yl-ethyl)-isothiazolo[5,4-d] pyrimidin-3-one

Using the procedure of Example 20, 14.0 g (41.6 mmol) of4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid(2-pyridin-2-yl-ethyl)-amide were treated with 10.6 g (41.7 mmol) ofiodine to give 12.7 g of the title compound after recrystallization fromethanol, mp 132°-133° C.

EXAMPLE 31

6-Piperidin-1-yl-2-(2-pyridin-2-yl-ethyl)-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 33.0 g (96.2 mmol) of4-mercapto-2-piperidin-1-yl-pyrimidine-5-carboxylic acid(2-pyridin-2-yl-ethyl)-amide were treated with 24.4 g (96.1 mmol) ofiodine to give 21.4 g of the title compound after recrystallization fromaqueous ethanol, mp 109°-110° C.

EXAMPLE 32

6-Piperidin-1-yl-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 20.8 g (87.4 mmol) of4-mercapto-2-piperidin-1-yl-pyrimidine-5-carboxylic acid amide weretreated with 22.2 g (87.4 mmol) of iodine to give 14.37 g of the titlecompound after recrystallization from dimethylformamide, mp 268°-269° C.

EXAMPLE 33

6-Morpholin-4-yl-2-(2-piperidin-1-yl-ethyl)-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 5.2 g (14.8 mmol) of4-mercapto-2-morpholin-4-yl-pyrimidine-5-carboxylic acid(2-piperidin-1-yl-ethyl)-amide were treated with 3.81 g (15.0 mmol) ofiodine to give 2.6 g of the title compound after recrystallization fromaqueous isopropanol, mp 98°-100° C.

EXAMPLE 34

6-Dimethylamino-2-(2-pyridin-2-yl-ethyl)-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 7.5 g (24.8 mmol) of2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid(2-pyridin-2-yl-ethyl)-amide were treated with 6.4 g (25.2 mmol) ofiodine to give 4.21 g of the title compound after recrystallization fromisopropanol, mp 134°-136° C.

EXAMPLE 35

6-Dimethylamino-2-(2-piperidin-1-yl-ethyl)-isothiazolo[5,4-d]pyrimidin-3-one

Using the procedure of Example 20, 6.2 g (20.1 mmol) of2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid(2-piperidin-1-yl-ethyl)-amide were treated with 5.08 g (20.0 mmol) ofiodine to give 5.31 g of the title compound after recrystallization fromethyl acetate, mp 128°-129° C.

Additional isothiazolones which can be made utilizing the processesdescribed above include the following:

    __________________________________________________________________________     ##STR24##                                                                

    __________________________________________________________________________     ##STR25##                                                                                    ##STR26##                                                                                     ##STR27##                                                                                  ##STR28##                        __________________________________________________________________________     ##STR29##                                                                                    ##STR30##                                                                                     ##STR31##                                                                                  ##STR32##                         ##STR33##                                                                                    ##STR34##                                                                                     ##STR35##                                                                                  ##STR36##                         ##STR37##                                                                                    ##STR38##                                                                                     ##STR39##                                                                                  ##STR40##                         ##STR41##     CH.sub.2 CO.sub.2 H                                                                            ##STR42##                                                                                  ##STR43##                         ##STR44##                                                                                    ##STR45##                                                                                     ##STR46##   CH.sub.2 CH.sub.2 CO.sub.2 H       ##STR47##                                                                                    ##STR48##                                                                                     ##STR49##                                                                                  ##STR50##                         ##STR51##                                                                                    ##STR52##                                                                                     ##STR53##                                                                                  ##STR54##                         ##STR55##                                                                                    ##STR56##                                                                                     ##STR57##   CH.sub.2 CH.sub.2 SO.sub.3 H                                      ##STR58##   CH.sub.3                           ##STR59##                                                                                    ##STR60##                                                                                     ##STR61##                                                                                  ##STR62##                         ##STR63##                                                                                    ##STR64##                                                                                     ##STR65##                                                                                  ##STR66##                         ##STR67##                                                                                    ##STR68##                                                                                     ##STR69##                                                                                  ##STR70##                         ##STR71##                                                                                    ##STR72##                                                                                     ##STR73##   CH.sub.2 CO.sub.2 H                ##STR74##                                                                                    ##STR75##                                                                                     ##STR76##                                                                                  ##STR77##                         ##STR78##                                                                                    ##STR79##                                                                                     ##STR80##                                                                                  ##STR81##                         ##STR82##                                                                                    ##STR83##                                                                                     ##STR84##                                                                                  ##STR85##                         ##STR86##                                                                                    ##STR87##                                                                                     ##STR88##                                                                                  ##STR89##                         ##STR90##                                                                                    ##STR91##                                                                                     ##STR92##                                                                                  ##STR93##                         ##STR94##                                                                                    ##STR95##                                                                                     ##STR96##                                                                                  ##STR97##                         ##STR98##                                                                                    ##STR99##                                                                                     ##STR100##  CH.sub.2 CO.sub.2 H                ##STR101##                                                                                   ##STR102##                                                                                    ##STR103##                                                                                 ##STR104##                        ##STR105##                                                                                   ##STR106##                                                                                    ##STR107##                                                                                 ##STR108##                        ##STR109##                                                                                   ##STR110##                                                                                    ##STR111##                                                                                 ##STR112##                       __________________________________________________________________________

Additional specific isothiazolones according to this invention includethe following:

    ______________________________________                                         ##STR113##                                                                   Example                                                                              R.sup.1   R.sup.2  R.sup.5                                             ______________________________________                                        36     H         H        CHiPrCOOH                                           37     H         H        n-hexyl                                             38     H         H        CH.sub.2 COOEt                                      39     H         H                                                            phenyl                                                                        40     H         H        4-acetylphenyl                                      41     H         H        acetyl                                              42     H         H        benzoyl                                             43     H         H        C(S)NH phenyl                                       44     H         H        4-chlorobenzoyl                                     45     H         H        4-nitrobenzoyl                                      46     H         H        CO(CH.sub.2).sub.4 CH.sub.3                         47     H         H        COCH.sub.2 phenyl                                   48     H         H                                                                                       ##STR114##                                         49     H         H        4-methoxybenzoyl                                    50     H         H        1-hydroxycarbonyl-                                                            2-methylbutyl                                       51     H         H        2-ethoxycarbonyl                                                              benzoyl                                             52     H         H        2-chlorobenzoyl                                     53     H         H        4-methyl-2-pyridyl                                  54     H         H        5-nitrothiazolon-2-yl                               55     H         H        2-(4-nitrophenyl)-2-                                                          hydroxy-1-hydroxy                                                             methylethyl                                         56     H         H        3-hydroxycarbonyl                                                             propyl                                              57     H         H        2-hydroxycarbonyl                                                             benzyl                                              58     H         H        2-pyrrolidin-1-ylethyl                              59     5-CH.sub.3 O                                                                            6-CH.sub.3 O                                                                           2-(2-pyridyl)ethyl                                  60     H         H        2-(2-piperidyl)ethyl                                61     H         H        3-(1-piperidyl)propyl                               62     H         H        4-hydroxycarbonyl                                                             methylphenylbenzyl                                  63     H         H        4-methoxybenzyl                                     64     H         H        4-methoxyphenyl                                     65     H         H        2,4-dichlorophenyl                                  66     H         H        2,4-dichlorobenzyl                                  67     H         H        3,4-dichlorophenyl                                  68     H         H        3,4-dichlorobenzyl                                  69     H         H        4-chlorophenyl                                      70     H         H        4-chlorobenzyl                                      71     H         H        4-(N-acetylamino)                                                             phenyl                                              72     H         H        4-(N-acetylamino)                                                             benzyl                                              73     H         H        4-ethoxycarbonylphenyl                              74     H         H        4-ethoxycarbonylbenzyl                              75     H         H        4-tert-butylphenyl                                  76     H         H        4-tert-butylbenzyl                                  77     H         H        4-trifluoromethyl                                                             phenyl                                              78     H         H        4-trifluoromethyl                                                             benzyl                                              79     H         H        4-biphenyl                                          80     H         H        4-phenylbenzyl                                      81     H         H        4-nitrobenzyl                                       82     H         H        cyclopropyl                                         83     H         H        cyclopropylmethyl                                   84     H         H        2-phenylethyl                                       85     H         H        cyclohexyl                                          86     H         H        cyclohexylmethyl                                    87     H         H        4-aminosulfonylphenyl                               ______________________________________                                         ##STR115##                                                                   Ex-                                                                           ample R.sup.1   R.sup.2    R.sup.5    mp °C.                           ______________________________________                                        88    H         H          n-propyl                                           89    H         H          2-(2-pyridyl)ethyl                                 90    H         H          2-(N,N-diethyl-                                                               amino)ethyl                                        91    7-chloro  8-chloro   dimethylamino-                                                                           241-242                                                            ethyl                                              92    6-methoxy 9-chloro   2-dimethylamino-                                                                         172-173                                                            ethyl                                              93    H         7-methoxy  2-dimethylamino-                                                                         175-176                                                            ethyl                                              94    H         8-methoxy  2-dimethylamino-                                                                         155-156                                                            ethyl                                              95              7,8-methylene                                                                            3-dimethylamino-                                                                         160-161                                                 dioxy      propyl                                             96              7,8-methylene                                                                            2-pyrrolidinoethyl                                                                       185-186                                                 dioxy                                                         97              7,8-methylene                                                                            2-morpholinoethyl                                                                        200-202                                                 dioxy                                                         98    H         8-chloro   2-dimethylamino-                                                                         214-215                                                            ethyl                                              99              7,8-methylene                                                                            2-acetamidoethyl                                                                         >260                                                    dioxy                                                         100   7-chloro  8-methoxy  2-dimethylamino-                                                                         226-227                                                            ethyl                                              ______________________________________                                         ##STR116##                                                                   Example R.sup.1                                                                             R.sup.2       R.sup.5                                           ______________________________________                                        101     H     6-piperidino  2-(N,N-diethylamino)ethyl                         102     H     6-piperidino  2-(2-pyridyl)ethylhydro                                                       chloride                                          103     H     6-dimethylamino                                                                             2-piperidylmethyl                                 104     H     6-pyrrolidino 2-(2-pyridyl)ethyl                                ______________________________________                                         ##STR117##                                                                   Example R.sup.1                                                                             R.sup.2          R.sup.5                                        ______________________________________                                        105     H     6-phenylsulfonyl 2-dimethylamino                                                               ethyl                                          106     H     6-chloro         methyl                                         107     H     6-trifluoromethyl                                                                              cyclopropyl                                    108     H     6(3,4-dimethoxyphenyl)                                                                         2-dimethylamino                                                               ethyl                                          ______________________________________                                         ##STR118##                                                                   Example   R.sup.1                                                                              R.sup.2                                                                              R.sup.5       mp °C.                           ______________________________________                                        109       H      H      2-dimethylaminoethyl                                                                        86-87                                   ______________________________________                                    

The compounds of the present invention cause the extrusion of zinc fromthe nucleocapsid protein (NCp7) of HIV-1. The NC protein is highlyconserved among all retroviruses (South T., Blake P., et al.,Biochemistry, 1990;;29:7786) and is essential for viral infectivity(Aldovini A. and Young R., J. Virology, 1990;64:1920 and Gorelick R.,Nigida S., et al., J. Virology, 1990;64:3207). The zinc is normally heldin NC proteins by 1 or 2 zinc fingers. In the case of HIV-1, 2 zincfingers are present (Summers M., South T., et al., Biochemistry,1990;29:329) and are involved specifically with the PSI site on viralRNA which controls the packaging of viral RNA. Interference of thispackaging causes the formation of non-infectious virions (Dannull J.,Surovoy A., et al., EMBO, 1994;13:1525). It has previously been shownthat compounds that cause zinc extrusion have potent anti-HIV activityin multiple cell lines and against all retroviruses (Rice W., SchaefferC., et al., Nature, 1993;361:473).

A fluorescence-based assay has been developed to monitor the ejection ofzinc from purified HIV-1 NCp7. The fluorophore,N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (TSQ), has an increasedfluorescent signal upon bonding zinc ion in solution. The NCp7 proteincontaining 2 Zn-fingers and 2 Zn ions is incubated with drug causing theextrusion of Zn ions. The released Zn is then sequestered by the TSQ andthe increased fluorescence monitored relative to control. The assay wasperformed as follows: 10 μM compound was added to 2.8 μM NCp7 and 47 μMTSQ in 20 μL of pH 7.4 buffer at 26° C. for 90 minutes. Fluorescence(excitation 355 nM emission 400 nM) was monitored versus time. Controlswere the NCp7 under assay conditions without drug, and apo NCp7 (no Zn)with drug. The % Zn extrusion was calculated based on the actualfluorescence measured divided by the fluorescence of all theoretical Znextruded (5.6 μM)×100.

Electrospray ionization mass spectral analysis was also performed. Using40 μM NCp7 in ammonium acetate buffer at pH 6, 320 μM4-(3-oxo-3h-benzo[d]isothiazol-2-yl)benzenesulfonamide (Example 1) inacetonitrile was added. After 3 minutes, a mass peak at 6360 (100%)corresponding to apo NCp7 (loss of 2 Zn) appeared. In addition, a peakat 6740 corresponding to the NCp7+308+Zn appeared. This peak representsthe NCp7 with one zinc extruded and a covalently attached compound of308 MW corresponding exactly to the MW of Example 1 indicating theextrusion of zinc and the formation of a covalent bond between thecysteine of the zinc finger and the isothiazolone.

The test systems utilized to establish the cellular antiviral activityof the isothiazolones of Formula I are well recognized in the art andare routinely employed for such purpose. For example, the assay utilizedto evaluate the compounds activity against the HIV virus is thatemployed by the U.S. National Cancer Institute as described by WeislowO. S., et al., J. Natl. Cancer Inst., 1989;81:577-586, incorporatedherein by reference.

The procedure is designed to detect agents acting at any stage of thevirus reproductive cycle. The assay basically involves the killing of T4lymphocytes by HIV. Small amounts of HIV are added to cells, and atleast two complete cycles of virus reproduction are necessary to obtainthe required cell killing. Agents which interact with virions, cells, orvirus gene-products to interfere with viral activities will protectcells from cytolysis. The system is automated in several features toaccommodate large numbers of candidate agents, and is generally designedto detect anti-HIV activity. However, compounds which degenerate or arerapidly metabolized in the culture conditions may not show activity inthis screen.

Another test system utilized to evaluate the invention compounds iscalled HIV H9 assay. The HIV H9 cell assay measures the inhibitorconcentration required to suppress HIV-1 virus replication. In thissystem, viral growth occurs through multiple rounds of the life-cycle.Any suppression of the replication kinetics results in a geometricdecrease in virus production. As a result, this assay is a sensitivemeans of measuring the ability of a compound to inhibit HIV-1 viralreplication.

The H9 T-cell line is batch infected with HIV virus at an MOI of 0.01.After 2 hours absorption, the cells are washed, resuspended inRPMI-1640/10% fetal calf serum, and seeded at 5×10-3 cells/well of a96-well plate. A duplicate plate of uninfected H9 cells is prepared forthe cytotoxicity assay. Drugs are serially diluted 1/3.16 in DMSO,transferred to media at an 8× concentration, and then added to thecultures in triplicate. The final DMSO concentration of 0.002 (0.2%).

Viral production is measured by RT assay and cytotoxicity is measured byXTT assay at 7 days post-infection. The RT assay is performed as amodification of Borroto-Esoda and Boone, J. Virol., 1991;65:1952-1959and quantitated using a Molecular Dynamics Phosphoimager with Imagequantsoftware. The XTT assay is performed as a modification of Roehm, et al.,J. Immuno Methods., 1991;142:257-265 and quantitated using a molecularDevices Thermomax plate reader with Softmax software.

Data is electronically transferred to a Microsoft Excell spreadsheet foranalysis. The RT assay values equivalent to 50% and 90% inhibition ofvirus production are calculated from the untreated controls. Theconcentrations of inhibitor required to produce these values (IC₅₀ andIC₉₀) are interpolated from data points flanking these RT activities.The XTT assay values equivalent to 50% cytotoxicity are calculated fromthe untreated controls. The concentrations of inhibitor required toproduce this value are interpolated from data points flanking these XTTvalues.

Yet another test system employed to determine antiviral activity iscalled the CEM cell assay.

T4 lymphocytes (CEM cell line) are exposed to HIV at a virus to cellratio approximately 0.05, and plated along with noninfected controlcells in 96-well microliter plates.

Candidate agent is dissolved in dimethyl sulfoxide (unless otherwisenoted), then diluted 1:200 in cell culture medium. Further dilutions(half-log₁₀) are prepared before adding to an equal volume of mediumcontaining either infected or noninfected cells.

Cultures are incubated at 37° in a 5% carbon dioxide atmosphere for 6 or7 days. The tetrazolium salt, XTT, is added to all wells, and culturesare incubated to allow formazan color development by viable cells J.National Cancer Institute, 1989;81:577-586. Individual wells areanalyzed spectrophotometrically to quantitate formazan production, andin addition are viewed microscopically for detection of viable cellsconfirmation of protective activity.

Drug-tested virus-infected cells are compared with drug-treatednoninfected cells and with other appropriate controls (untreatedinfected and untreated noninfected cells, drug-contain wells withoutcells, etc.) on the same plate. Data are reviewed in comparison withother tests done at the same time and a determination about activity ismade.

Table 1 below presents the results of testing several of the inventioncompounds in zinc extrusion assay described above. The compounds wereevaluated for their ability to cause the extrusion of zinc fromnucleocapsid protein NCp7 (expressed as % relative to control).

                  TABLE 1                                                         ______________________________________                                        Zn Extrusion From the Zn Fingers of                                           HIV-1 Nucleocapsid Protein (NCp7)                                             Compound of  % Zn Extrusion Relative                                          Example      to Control                                                       ______________________________________                                        EDTA.sup.a   10                                                               Preparation 29                                                                             5.8                                                               1           100                                                               2           30                                                               13           75                                                               14           71                                                               15           97                                                               17           78                                                               18           100                                                              25           89                                                               ______________________________________                                         .sup.a  EDTA removes approximately 10% of the Zn from the Zn finger in 24     hours (Rice W. and Schaeffer C., et al.,  Nature, 1993;361:473)          

Table 2 below presents data for several invention compounds whenevaluated in the H9 and the CEM cell assays. The data establish thecompounds of this invention are effective against the HIV virus whenevaluated in both test systems.

                  TABLE 2                                                         ______________________________________                                        Anti-HIV Activity                                                             Compound of    CEM Cell Assay                                                 Example        EC.sub.50  (μM).sup.a                                                                 TC.sub.50  (μM).sup.b                            ______________________________________                                         1             5.1        21                                                   2             14         >100                                                14             21         >100                                                17             5.8        >100                                                25             5.8        69                                                  ______________________________________                                         .sup.a Effective concentration which protects cells from viral cytopathic     effects                                                                       .sup.b Toxic concentration which inhibits the growth of cells 50% relativ     to control                                                               

The compounds of the invention have utility against a wide range ofretroviral infections, and accordingly, have broad application. Examplesof possible viruses that may be suitable for treatment using the presentinvention include Type C and Type D retroviruses, HTLV-1, HTLV-2, FLV,SIV, MLV, BLV, BIV, equine infectious viruses, anemia viruses, aviansarcoma viruses, and the like.

The isothiazolones of Formula I are also effective for treatinginflammation and atherosclerosis. A characteristic feature ofatherosclerosis is the accumulation of cholesteryl ester engorged fromfoam cells. Foam cells are derived from circulating monocytes whichinvade artery walls in response to hypercholesterolemia, and mature intotissue macrophages. The enzyme 15-lipoxygenase (15-LO) has beenimplicated in inflammatory disorders and in the origin and recruitmentof foam cells (see Harats, et al., Trends Cardioivasc. Med.,1995;5(1):29-36. This enzyme is capable of oxidizing esterifiedpolylnoic fatty acids, such as those found in phospholipids. Treatmentof experimental animals with antioxidants which reduce hydroperoxidesproduced by 15-LO has been shown to retard the progression ofatherosclerotic lesions. Accordingly, administering compounds whichinhibit 15-LO is an effective way to treat and prevent atherosclerosis.The isothiazolones of Formula I are effective inhibitors of 15-LO whenevaluated in standard assays routinely utilized to measure 15-LOactivity. Specifically, representative compounds were evaluated by themethods described by Auerbach, et al., Analytical Biochemistry,1992;201:375-380. Two in vitro assays were utilized, both utilizingrabbit reticulocyte 15-LO, and linoleic acid as substrate, toenzymatically produce a peroxide oxidation product known as 13(S)-HPODE.N-Benzoyl leucomethylene blue was utilized as a colorimetric reagent fordetection and quantification of the peroxide formation. Also, HPLC wasutilized to quantify the oxidation following incubation at 4° C. for 10minutes.

The 15-LO inhibitory activity of representative isothiazolones ispresented in Tables 3 and 4. Table 3 gives the concentration of compoundrequired to inhibit 50% of the activity of 15-LO (IC₅₀) when measured bythe HPLC method of Auerbach, et al. Table 4 gives the percent inhibitionof 15-LO activity when evaluated by the colorimetric method.

                  TABLE 3                                                         ______________________________________                                        HPLC Assay of 15-LO Inhibition                                                Compound of Example                                                                             IC.sub.50  (μM)                                          ______________________________________                                        23                0.4                                                         24                0.3                                                         27                0.27                                                        28                0.76                                                        29                0.39                                                        30                0.29                                                        31                1.3                                                         32                3.2                                                         33                0.12                                                        34                1.7                                                         35                0.16                                                        ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Colorimetric Assay of 15-LO Inhibition                                        Compound of Example                                                                             % Inhibition                                                ______________________________________                                        1                 35 @ 10 μM                                               3                 75 @ 10 μM                                               21                95 @ 10 μM                                               50                >10 μM                                                   59                >10 μM                                                   91                >10 μM                                                   93                >10 μM                                                   94                >10 μM                                                   95                >10 μM                                                   96                >10 μM                                                   97                >10 μM                                                   108               65 @ 10 μM                                               109               22 @ 10 μM                                               ______________________________________                                    

The compounds of Formula I are therefore useful for treatingatherosclerosis by virtue of their ability to inhibit 15-LO.

In a further embodiment of this invention, the compounds can beformulated into compositions suitable for applying to surfaces such aswood, metal, ceramic, and the like, and for administering to animals,including humans, for treating and preventing diseases caused byviruses, as well as inflammation and atherosclerosis. The compounds canbe formulated for administration by any route, for instance orally,parenterally, topically, and rectally. For oral administration, forexample, an invention compound can be mixed with an inert diluent orwith an assimilable edible carrier, or it may be enclosed in a hard orsoft shell gelatin capsule, or it may be compressed into tablets, or itmay be incorporated directly with the food of the diet. For oraltherapeutic administration, the active compound may be incorporated withexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 1% by weightof active compound. The percentage of the compositions and preparationsmay, of course, be varied and may conveniently be between about 5% toabout 80% of the weight of the unit. The amount of active compound insuch therapeutically useful compositions is such that a therapeuticallyeffective dosage will be obtained. Preferred compositions orpreparations according to the present invention are prepared so that anoral dosage unit form contains between about 5 and 1000 mg of activecompound, and ideally about 25 to about 750 mg.

The tablets, troches, pills, capsules, and the like may also containcommon pharmaceutical excipients such as binders, sweeteners, and thelike. Typical binders include gum tragacanth, acacia, corn starch, andgelatin, as well as excipients such as dicalcium phosphate. Typicaldisintegrating agents include corn starch, potato starch, alginic acid,and the like. A commonly used lubricant is magnesium stearate. Typicalsweetening agents are sucrose, lactose, or saccharin, and flavoringagents such as peppermint, oil of wintergreen, or cherry flavoring canbe utilized. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar, or both. A syrup or elixir may containthe active compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye, and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially nontoxic in theamounts employed.

The isothiazolone compounds of the invention can also be formulated fortopical administration, for instance as patches, salves, creams,ointments, and the like. Agents commonly utilized to enhance transdermalpassage can also be employed. The compounds can also be formulated withwaxes and the like for convenient rectal administration.

The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations may contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the form must be sterile andmust be fluid to the extent that easy syringability exists. It must bestable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms such asbacteria and fungi. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, a polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. The properfluidity can be maintained, for example, by the use of a coating such aslecithin; by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. the prevention of theaction of microorganisms can be brought about by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like. In many cases, it will bepreferable to include isotonic agents, for example, sugars or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

As used herein, "pharmaceutically acceptable carrier" includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like. The useof such media and agents for pharmaceutical active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the novel dosageunit forms of the invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such an active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedisclosed. The term "effective amount" means that quantity ofisothiazolone which has a positive therapeutic effect for treating theviral infection, the inflammation, or the atherosclerosis which affectsthe mammal to be treated. A unit dosage form can, for example, containthe principal active compound in amounts ranging from about 5 to about1000 mg, with from about 25 to about 750 mg being preferred. A typicaldose will be about 50 to about 500 mg. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients. The unit dosages typically will be administered from one tofour times per day, or as otherwise needed to effect treatment of thedisease state.

In a further embodiment, the isothiazolones are utilized in combinationwith other agents having antiviral activity. For example, commonly usedagents include acyclovir, AZT (azidothymidine, zidovudine), ribavirin,vidarabine, ganciclovir dideoxyinosine (ddI), and the like. Theisothiazolones will be administered in combination with such otherantiviral agents generally in their respective normal dosing regimens.The specific combinations to be utilized, the respective amountsadministered, and the frequency of dosing will, of course, be determinedby the attending medical technician or physician in view of theparticular agents employed, the specific condition being treated, andthe severity of the disease.

The following examples further illustrate the formulations of thisinvention.

EXAMPLE 110

Soft gelatin capsules were prepared using the following ingredients:

    ______________________________________                                                            Quantity                                                                      (mg/capsule)                                              ______________________________________                                        Compound of Example 1                                                                             250.0                                                     Butylated hydroxyanisole B.P.                                                                     0.05                                                      Fractionated Coconut Oil B.P.                                                                     70.0                                                                          320.05                                                    ______________________________________                                    

The above ingredients were mixed and filled into a soft gelatin capsule,the shell components of which were gelatin and glycerine. The capsulesare administered at the rate of one to four times a day.

EXAMPLE 111

Tablets are prepared using the following components:

    ______________________________________                                        Compound of Example 5 500      mg                                             Microcrystalline Cellulose                                                                          200      mg                                             Sodium Carboxymethyl Starch                                                                         20       mg                                             Magnesium Stearate    4        mg                                             Butylated Hydroxyanisole B.P.                                                                       0.002    mg                                             ______________________________________                                    

The ingredients were blended to uniformity and compressed into a tabletfor oral administration. One to four tablets are administered daily fortreatment of viral infections.

EXAMPLE 112

An aerosol is prepared as follows:

    ______________________________________                                        Compound of Example 4                                                                             100        mg                                             Propylene glycol    20         mg                                             Dichlorotetrafluoroethane                                                                         600        mg                                             (Propellant 14)                                                               Dichlorodifluoromethane                                                                           500        mg                                             (Propellant 12)                                                               ______________________________________                                    

The components are mixed at -20° C. and placed into a sealed canequipped with a metering device.

EXAMPLE 113

A solution is prepared as follows:

    ______________________________________                                        Compound of Example 6                                                                            5         mg                                               Water              1         L                                                1N HCl             20        mL                                               ______________________________________                                    

The ingredients are mixed to form a solution which can be utilized towash shower stalls in order to prevent and eliminate bacterial growth.

A further embodiment of this invention is a method of treating,preventing, and combatting viral infections. The method comprisesadministering an antivirally effective amount of a compound of thisinvention to a subject or surface in need of treatment. For example, thecompounds of Formula I can be applied to shower stalls and public placesin order to prevent, control, and combat vital growth. The compounds canbe administered to animals, especially humans, to treat and preventviral infections As noted above, an effective amount of the activecompound generally is about 5 to about 1000 mg per dosage unit, andideally about 25 to about 750 mg.

The active ingredients of the therapeutic compositions and the compoundsof the present invention exhibit excellent anti-retrovirus activity whenadministered in amounts ranging from about 1.0 to about 100 mg/kg ofbody weight per day. A preferred dosage regimen for optimum resultswould be from about 2.0 to about 50 mg/kg of body weight per day, andsuch dosage units are employed so that a total of from about 0.2 toabout 3.0 g of the active compound for a subject of about 70 kg of bodyweight are administered in a 24-hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response and is preferablyadministered one to four times a day in dosages of about 250 to about750 mg per administration. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage is that the active compound may be administered in aconvenient manner such as by the oral, intravenous (where watersoluble), intramuscular or subcutaneous routes.

The active compounds can be formulated as aqueous solutions andsuspensions for washing surfaces such as wood, steel, ceramic, and thelike in order to eliminate and control growth due to viruses.

Another embodiment of the invention is a method for treatingatherosclerosis in mammals suffering therefrom and in need of treatment.The compounds are effective in inhibiting the activity of15-lipoxygenase, and as such can be administered to a mammal, includinga human, to effectively diminish and treat atherosclerosis. Thecompounds will be administered at a dose which is effective to treatatherosclerosis, typically from about 1.0 to about 100 mg/kg of bodyweight of the subject being treated.

The compounds also are useful for treating inflammation, for example,swelling due to injuries, swelling around bones and joints, and thelike. The compounds will be administered to an animal suffering frominflammation in an amount that is effective to treat the inflammation.Typical doses will be from about 1.0 to about 100 mg/kg of body weight.

We claim:
 1. A compound having Formula V ##STR119## wherein: R¹ and R²independently are hydrogen, halo, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl,substituted or unsubstituted phenyl-(CR⁶ R⁷)_(m) -, substituted orunsubstituted Het(CR⁶ R⁷)_(m) -, O--C₁ -C₆ alkyl, hydroxy, cyano, NR³COR⁴, CO₂ R³, CONR³ R⁴, S(O)_(m) R³, SO₃ H, S(O)_(m) NR³ R⁴, COR³ ortaken together are oxo (O═) or methylenedioxy(--O--CH₂ --O--);m is 0, 1,or 2; R³ and R⁴ independently are hydrogen, C₁ -C₆ alkyl, C₃ -C₆cycloalkyl, Het (CR⁶ R⁷)_(m) -, or phenyl-(CR⁶ R⁷)_(m) -; R⁵ is C₁ -C₆alkyl, COC₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, substituted phenyl-(CR⁶R⁷)_(m) -, unsubstituted or substituted Het(CR⁶ R⁷)_(m) -, wherein thealkyl, COC₁ -C₆ alkyl and cycloalkyl groups are substituted with 1 to 3groups selected from NR³ COR⁴, CO₂ R³, CONR³ R⁴, S(O)_(m) R³, SO₃ H,S(O)_(m) NR³ R⁴ and COR³, and wherein the phenyl and Het groups mayoptionally be substituted with halo, hydroxy, NR³ R⁴, NR³ COR⁴, CO₂ R³,CONR³ R⁴, S(O)_(m) R³, SO₃ H, S(O)_(m) NR³ R⁴, and COR³ ; R⁶ and R⁷independently are hydrogen, C₁ -C₆ alkyl, CO₂ R³, hydroxy, CONR³ R⁴, orcyano; provided that R⁵ is other than substituted phenyl-(CR⁶ R⁷)_(m) -when the substituent on the phenyl ring is alkyl, halo, alkoxy, or NR³R⁴ ; and the pharmaceutically acceptable salts and solvates thereof. 2.A compound of claim 1 wherein R⁵ is ##STR120##
 3. A compound of claim 2wherein R² is hydrogen.
 4. A compound of claim 3 wherein R⁵ is##STR121##
 5. The compound of claim 4 whichis[S-(R*,R*)]-3-Methyl-2-(3-oxo-3H-benzo[d] isothiazol-2-yl)pentanoicacid; (S)-4-methyl2-(6-Methoxy-3-oxo-3h-benzo[d]isothiazol-2yl)-pentanoic acid;(S)-4-Methyl-2-(5-fluoro-3-oxo-3h-benzo[d] isothiazol-2-yl)-pentanoicacid; and (S)-4-Methyl-2-(6-methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-pentanoic acid.
 6. A compound of claim 3 wherein R⁵ is##STR122##
 7. A compound of claim 6 wherein R³ is hydrogen.
 8. Thecompound of claim 7 whichisN-Acetyl-4-(3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide.
 9. Acompound of claim 7 wherein R⁴ is hydrogen.
 10. The compound of claim 9which is4-(3-Oxo-3H-benzo[d]isothiazol-2-yl) benzenesulfonamide;4-(5-Methoxy-3-oxo-3h -benzo[d]isothiazol-2-yl)-benzenesulfonamide;4-(6-Methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide;4-(6-Fluoro-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide; and4-(5-Methyl-3-oxo-3h-benzo[d]isothiazol-2-yl)-benzenesulfonamide.
 11. Apharmaceutical formulation comprising a compound of claim 1 togetherwith a pharmaceutically acceptable carrier therefor.
 12. A formulationof claim 11 employing a compound of the formula ##STR123##
 13. Aformulation of claim 12 employing a compound wherein R¹ is hydrogen. 14.A formulation of claim 13 employing a compound wherein R⁵ is ##STR124##15. A formulation according to claim 14 comprising[S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid.16. A formulation according to claim 14 comprising4-(3-oxo-3H-benzo[d]isothiazol-2-yl)-benzenesulfonamide.